1. Field of the Invention
This invention relates generally to proliferative disorders such as cancer and, more specifically, to PR-domain containing genes and gene products that can be used to diagnose and treat proliferative disorders.
2. Background Information
Cancer is one of the leading causes of death in industrialized nations. Cancerous tumors result when a cell escapes from its normal growth regulatory mechanisms and proliferates in an uncontrolled fashion. Cells from the primary tumor generally metastasize to vital organs if treatment of the primary tumor is either not complete or not initiated early enough. Thus, early diagnosis and effective treatment of tumors is essential for survival.
Cancer involves the clonal replication of populations of cells that have gained competitive advantage over normal cells through the alteration of regulatory genes. Regulatory genes can be broadly classified into “oncogenes” which, when activated or overexpressed promote unregulated cell proliferation, and “tumor suppressor genes” which, when inactivated or underexpressed fail to prevent abnormal cell proliferation. Loss of function or inactivation of tumor suppressor genes is thought to play a central role in the initiation and progression of a significant number of human cancers.
A number of tumor suppressor genes have been identified that, when inactivated, are involved in the initiation or progression of human cancers. Known tumor suppressor genes include RB, p53, DCC, APC/MCC, NF1, NF2, WT1, VHL, BRCA1, MST1 and WAF1/CIP1. Approaches for treating cancer by modulating the function of several of these tumor suppressor genes, either with pharmaceutical compounds that target their encoded proteins, or by gene therapy methods, have yielded promising results in animal models and in human clinical trials.
Approaches for diagnosing and prognosing cancer by identifying mutations in tumor suppressor genes have also been developed. For example, identifying individuals containing germline mutations in known tumor suppressor genes has permitted the identification of individuals at increased risk of developing cancer. Such individuals are then closely monitored or treated prophylactically to improve their chance of survival. Identifying the pattern of alterations of known tumor suppressor genes in biopsy samples is also being used to determine the presence or stage of a tumor. Being able to determine whether a cancer is benign or malignant, or at an early or late stage of progression, provides the patient and clinician with a more accurate prognosis and can be used to determine and monitor the course of treatment.
One important family of tumor suppressor genes that has recently been identified are PR-domain containing genes. A “PR domain” is a motif of approximately 100 to 125 amino acids first identified as a region of homology between the Rb-binding zinc finger protein RIZ, and the transcriptional repressor protein PRD1-BF1/Blimp1, which promotes B-cell differentiation (Buyse et al., Proc. Natl. Acad. Sci. USA 92:4467-4471 (1995); Huang, Cell 78:9 (1994)). A PR domain motif is also found in the MDS1-EVI1 myeloid leukemia gene (Fears et al., Proc. Natl. Acad. Sci. USA 93:1642-1647 (1996)). PR domain-encoding genes have also been identified in other mammals and in lower organisms, including C. elegans and Drosophila, suggesting an evolutionarily conserved function for this domain.
Several observations indicate that PR-domain containing gene products are negative regulators of cell growth and tumorigenesis, whereas the PR-deficient products of these genes are involved in growth promotion and oncogenesis. For example, the PR region of MDS1-EVI1 is often disrupted by leukemia-associated chromosomal insertions and translocations. These disruptions result in loss of the PR-containing MDS1-EVI1 product and selective retention of the PR-deficient EVI1 product. In contrast, the PR-EVI1 product is overexpressed in some tumor cells, and acts as an oncogene (Morishita et al., Cell 54:831-840 (1988); Morishita et al., Proc. Natl. Acad. Sci. USA 89:3937-3941 (1992))
Similarly, the RIZ gene produces two products, a PR-containing protein, RIZ1, and a PR-deficient protein, RIZ2, which is generated from an internal promoter. RIZ1 is commonly absent or underexpressed in a number of human neoplasias, including breast cancer, neuroblastoma and lung cancer. In these cases, the PR-deficient product, RIZ2, is expressed at normal levels (He et al., Cancer Res. 58:4238-4244 (1998)). These results suggest that the PR-containing RIZ1 product is a negative regulator of cell proliferation and tumorigenesis, whereas maintenance of RIZ2 expression may be required for oncogenesis.
As further evidence that RIZ is a tumor suppressor gene, forced expression of the RIZ1 product in breast cancer cells causes cell cycle arrest at the G2/M phase of the cell cycle, and programmed cell death (He et al., Cancer Res. 58:4238-4244 (1998)). Additionally, consistent with a role of RIZ1 in growth suppression, mice in which RIZ1, but not RIZ2, is inactivated, are tumor prone.
A third PR domain-containing gene, PRDI-BF1/BLIMP1 is also likely to be a tumor suppressor gene. PRD1-BF1/BLIMP1 maps to the 6q21 region commonly deleted in non-Hodgkin's lymphoma (Mock et al., Genomics 37:24-28 (1996)) and is thus a strong candidate tumor suppressor for B-cell non-Hodgkin's lymphoma. Additionally, PRDI-BF1/BLIMP1 is a transcriptional repressor of c-Myc (Lin et al., Science 276:596-598 (1997)), which is an oncogene critically involved in B cell lymphoma.
In view of the importance of tumor suppressor genes and related molecules in the detection and treatment of cancer, there exists a need to identify additional tumor suppressor genes. In particular, in view of the established role of PR-domain containing genes as tumor suppressor genes, there exists a need to identify and characterize additional PR-domain family members. The present invention satisfies this need and provides related advantages as well.